Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium which is wide in prevalent range, strong in pathogenicity and high in morbidity and mortality. Once a human body is infected, symptoms such as fever, poor spirit and local infection are caused, the most common symptom is pulmonary infection, other symptoms include skin, urinary tract and pregnant woman's reproductive tract infections, the serious symptom is septicemia, so that length of stay of a patient is delayed, and life of the patient can be endangered without timely treatment. An investigation from Dutch in 2003 reveals that about 39% of slaughtered pigs contain ST398 type MRSA, and 27% of feeders carry pig-derived MRSA. Animal-derived MRSA ST398 can cause infection of humans contacting with animals. MRSA can resist all of 13 amide antibiotics and resist most of macrolide, aminoglycoside and fluoroquinolone antibacterial drugs and the like, leading to a fact that infection caused by this bacterium is difficult to treat and high in fatality rate.
Pleuromutilin (formula I) is produced by higher fungi Pleurotusmutilize (Fr.) Sacc. and Pleurotus Passecheranius Pilat, and is a tricylic diterpene compound having a combined (5-6-8)tricycle. The compounds and a ribosome 50S subunit interact to inhibit synthesis of bacterial proteins. The compounds have strong antibacterial activity on drug-resistant gram-positive bacteria, drug-resistant mycoplasma and partial gram-negative bacteria. The pleuromutilin compounds have a nuclear parent structure different from those of clinically common antibacterial drugs, and difficultly generate cross drug resistance with antibacterial drugs having other structures. Through modification of a pleuromutilin C14 side chain, two pleuromutilin veterinary antibacterial drugs Tiamulin and Valnemulin have entered a market at present.
As a first human pleuromutilin antibacterial drug, retapamulin was approved by Food and Drug Administration (FDA) of America to be marketed in 2007. It is mainly used for treatment of pustule atopic dermatitis caused by Staphylococcus aureus and Streptococcus pyogenes infections. Retapamulin has good antibacterial activity on multiple drug-resistant bacteria such as clinically common antibacterial drugs including oxacillin, erythrocin and mupirocin. It is also found that retapamulin more difficultly causes drug resistance of Staphylococcus aureus compared with traditional antibacterial drugs.
Since the mechanism of the pleuromutilin compound is different from that of antibiotics widely applied in clinic, there are few drug-resistance bacteria for pleuromutilin antibacterial drugs. Compared with dozens of drugs successfully developed based on the same nuclear parent with penicillin, cephalosphorin and floxacin antibacterial drugs, there are only three antibacterial drugs to be successfully developed based on pleuromutilin. The disclosure will provide a novel pleuromutilin compound having novel structures and strong antibacterial activity.
